A Strategy to Treat COVID-19 Disease with Targeted Delivery of Inhalable Liposomal Hydroxychloroquine: A Non-clinical Pharmacokinetic Study

  1. Tien-Tzu Tai
  2. Tzung-Ju Wu
  3. Huey-Dong Wu
  4. Yi-Chen Tsai
  5. Hui-Ting Wang
  6. An-Min Wang
  7. Sheue-Fang Shih
  8. Yee-Chun Chen

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Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly identified pathogen causing coronavirus disease 2019 (COVID-19) pandemic. Hydroxychloroquine (HCQ), an antimalarial and anti-inflammatory drug, has been shown to inhibit SARS-CoV-2 infection in vitro and tested in clinical studies. However, lung concentration (6.7 µg/mL) to predict the in vivo antiviral efficacy might not be achievable with the currently proposed oral dosing regimen. Further, a high cumulative doses of HCQ may raise concerns of systemic toxicity, including cardiotoxicity. Here, we described a non-clinical study to investigate the pharmacokinetics of a novel formulation of liposomal HCQ administrated by intratracheal (IT) instillation in Sprague-Dawley (SD) rats which achieved 129.4 µg/g (C max ) in the lung. Compared to unformulated HCQ administered intravenous (IV), liposomal HCQ with normalized dose showed higher (∼30-fold) lung exposure, longer (∼2.5-fold) half-life in lung, but lower blood exposure with ∼20% of C max and 74% of AUC and lower heart exposure with 24% of C max and 58% of AUC. In conclusion, the pharmacokinetics results in an animal model demonstrate the proof of concept that inhalable liposomal HCQ may provide clinical benefit and serve as a potential treatment for COVID-19.

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  1. ScreenIT

    SciScore for 10.1101/2020.07.09.196618: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementIACUC: All procedures involving animals were performed in TLC animal facility and in accordance with the ethical guidelines of Institutional Animal Care and Use Committee (IACUC) at TLC, Taiwan (#TLC20IACUC012).
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variableStudy Design: A total of 52 female SD rats (BioLASCO Taiwan Co., Ltd.) were assigned to one of three treatment groups: (1) HCQ-IV: 12 rats received a single dose of 0.590 mg HCQ sulfate per animal via IV injection; (2) HCQ-IT: 20 rats received a single dose of 0.590 mg HCQ sulfate per animal via intratracheal (IT) administration; and (3) liposomal HCQ-IT: 20 rats received a single dose of 0.284 mg liposomal HCQ sulfate per animal via IT administration.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    PK parameters of HCQ were calculated by a non-compartmental method using Phoenix® WinNonlin® (version 8.0).
    Phoenix®
    suggested: (Phoenix, RRID:SCR_003163)
    WinNonlin®
    suggested: None

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    A limitation of the current study is that the pharmacokinetics of liposomal HCQ were evaluated in a rat model using IT instillation to mimic the intended inhalation administration. The typical lung deposition efficiency with inhaled aerosols is very likely lower than that of the IT instilled microsprayed-droplets. Furthermore, it is suggested the aerosol-generating procedure (nebulization) on patients with known or suspected COVID-19 should be performed cautiously given that SARS-CoV-2 is highly contagious through the respiratory route (https://www.cdc.gov/coronavirus/2019-ncov/hcp/infection-control-recommendations.html) (15). Therefore, we have developed a disposable closed-loop system connected to the nebulizer to maximize the targeted delivery of inhaled liposomal HCQ while minimize the spreading and contaminating the air and environment (data not shown). In conclusion, this study in a rat model demonstrate the desirable pharmacokinetics of inhalable liposomal HCQ in vivo. It supports the working hypothesis that inhalable liposomal HCQ might serve as a potential treatment option for the delivery of HCQ for COVID-19 pulmonary disease by achieving targeted antiviral levels with less frequent dosing and at a relatively lower dose.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • No conflict of interest statement was detected. If there are no conflicts, we encourage authors to explicit state so.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

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  2. Version published to 10.1101/2020.07.09.196618 on bioRxiv